The broad, long-term objective of this application is to improve the effectiveness of management strategies for patients with malignant glioma, a disease process that results in >10,000 deaths annually in the U.S. Standard therapeutic approaches with surgery, external beam radiotherapy and chemotherapy have resulted in minimal survival gain and the lethality approaches 100%, with average survival ranging from 9 to 18 months, depending on various prognostic factors. The specific focus of this grant will be to continue previously initiated clinical trials, design and implement new strategies and carefully analyze data generated from a series of investigational Phase I/II trials in adult patients with malignant glioma. In order to realize meaningful results expeditiously, the investigational studies will be performed simultaneously at several institutions which constitute the North American Brain Tumor Consortium (NABTC). We intend to perform 6 to 8 trials annually, enrolling between 80 to 140 fully evaluable cases per year through the consortium. All patients will be evaluated and treated by a multidisciplinary team composed of neurosurgeons, oncologists, radiation oncologists, neuro-pathologists, neuroradiologists and clinical research nurses, with the data collected prospectively and monitored and evaluated by dedicated data managers and statisticians. In addition to this intense multidisciplinary clinical effort, the consortium arrangement will permit networking of ideas to allow creative cooperation and maintain the highest level of interest in translational laboratory-based clinical research. The NABTC agreement provides a rich resource of multiple tissue-banks and pharmacokinetic samples for sharing of tissue and serum specimens for ancillary laboratory-based studies and subsequent clinical correlations. Such correlations may include new developments in drug and radiation resistance, radiation sensitization, induction of apoptosis, signal transduction modulation, improvements in therapeutic radiation delivery techniques, better drug sequencing, superior understanding of chemotherapeutic metabolism under altered hepatic enzymologic conditions induced by steroids and anticonvulsants, incorporation of gene therapy in future trials, etc. The entire effort will be intimately linked with the ongoing interests, needs and support of the Cancer Therapy Evaluation Program and the Radiation Research Program of the Division of Cancer Treatment Diagnosis and Centers at the National Cancer Institute. [unreadable] [unreadable] [unreadable]